This invention relates to polyiodinated compounds useful as radiopaques and radiopharmaceuticals, and more specifically to polyiodinated arylaliphatic triglyceride analogs which are site-specific to the liver and hepatocytes.
The liver is the most common site for the development of metastatic disease, and can be seeded by primary neoplasms of diverse origin, such as the gastrointestinal tract, breasts, lungs, and lymphatics. Although the success of chemotherapy and surgical techniques has improved the prognosis of affected patients, it is known that reliable and early detection of the liver metastases is required if therapeutic measures are to be effective. Thus, early detection of small metastatic lesions has been a long-term goal of radiology and nuclear medicine.
Over the past several decades, significant advances have been made in systems which enable visualization of internal organs, such as the liver, by noninvasive procedures. Two of the most widely used imaging modalities, radiography and radioisotope scanning, owe much of their success to the development of suitable radiopaques and radiopharmaceuticals. A major pharmacological difference between radiopaques and radio-pharmaceuticals is that large doses of the former are required for opacification of soft tissue, whereas the latter are administered in tracer doses. The advent of computed tomography (CT), however, now offers the possibility of reducing this dosage differential, In contrast to conventional-X-ray imaging which reliably detects differences in tissue density of 5-10%, CT can detect differences as small as 0.5%.
Although X-ray CT using water-soluble, urographic contrast agents is currently the most accurate, noninvasive radiologic examination routinely used for the evaluation of hepatic masses, this imaging modality has definite limitations in the detection of lesions smaller than 2 cm. The major limitation is due largely to the rapid egress of the urographic agents from the vascular system into the extracellular spaces, thus reducing the contrast differential between the tumor and the normal liver tissue. Indeed, since many metastatic lesions would be smaller than 2 cm in patients with incipient liver disease, it is imperative that contrast agents specifically localize within the normal cells of the liver, and remain there for a sufficiently long period of time to enable high quality images to be obtained by CT. Thus, there is a need for liver-specific contrast agents for CT which possess the target organ specificity that the urographic agents lack. Moreover, the urographic agents achieve liver enhancement by uptake by the reticuloendothelial (RE) system. However, the majority of metastases involve primarily liver hepatocytes, and therefore the efficacy of RE-specific agents for CT detection of small hepatic matastases is limited. Thus, there is also a need for hepatocyte selective agents.
Alternatives to the urographic agents currently in wide-spread use have been evaluated for greater organ selectivity and longer duration of contrast enhancement. These agents include ethiodized oil emulsions (EOE 13), radiopaque liposomes, iodinated starch particles, and iodipamide ethyl ester. As is the case with urographic agents, these agents have had only limited success, at least partially as a result of the fact that they operate by uptake into the RE system.
Iodine has played an important role in radiopaque and radiopharmaceutical diagnostic compositions, such as those referenced above. Iodine not only imparts the necessary electron density to radiopaques; but can, in its various isotope states (e.g., I.sup.123, I.sup.125, and I.sup.131), emit the gamma radiation essential for gamma-camera scintigraphy. Currently, however, the most widely used liver scintigraphy agent is .sup.99m Tc-sulfur colloid. This agent is removed from the circulation by phagocytic action of RE cells. The static anatomic image thus obtained proves useful in the location of primary and secondary lesions as small as 2-3 cm in diameter, but has no utility in assessing hepatocyte function. Hepatocyte function can, however, be studied by monitoring the uptake and clearance of .sup.131 I-Rose Bengal (tetraiodotetrachlorofluorescein), a dye which is extracted by hepatocytes and, under normal conditions, is quickly secreted into the bile. This agent, however, is disadvantageously characterized by a slow rate of hepatic to intestinal output, poor imaging characteristics, and high radiation doses associated with .sup.131 I. Consequently, there is a need for both a hepatocyte-specific scintigraphy agent and a liver-specific CT agent.
It is, therefore, an object of the invention to provide improved radiologic agents which are liver specific for CT purposes and hepatocyte selective for scintigraphy purposes.
It is another object of the invention to provide improved radiologic agents which are liver specific and will reveal metastatic lesions smaller than 2 cm.
It is a further object of the invention to provide improved radiologic agents which are hepatocyte selective rather than reticuloendothelial system selective.
It is also an object of the invention to provide improved radiologic agents which will opacify soft tissue when administered in small doses.
It is an additional object of the invention to provide radiologic agents which will be physiologically acceptable and non-toxic.
It is still another object of the invention to provide improved radiologic agents which will remain in the target organs for residence periods of sufficient duration to enable high quality imaging.
It is yet another object of the invention to provide techniques for producing such improved radiologic agents.
It is additionally an object of the invention to provide iodine-containing radiologic agents which can be used as radiopaques, or which can be radio-tagged for use in scintigraphy.
It is yet another object of the invention to provide an improved technique for producing radio-tagged scintigraphy agents.
It is a yet further object of the invention to provide improved radiologic agents which are subject to hydrolysis and deiodination so that the radiologic agents will be cleared from the body of the patient to whom the radiologic agent has been administion within a reasonable period of time; but which will be stable enough to permit adequate residence time for good imaging by CT.
It is additionally a further object of the invention to provide an improved carrier vehicle for the radiologic agents which is site-specific and lipid-based.
It is still a further object of the invention to provide an improved technique for incorporating a radiologic agent in a lipid-based carrier vehicle.
It is yet a still further object of the invention to provide a radiologic agent/vehicle formulation which is isotonic and avoids the patient discomfort accompanying hyperosmolarity.